Some rooms in SAFC Biosciences’ (www.safcbiosciences.com) dry powder media manufacturing facility in Lenexa, KS, are named in honor of pioneers of cell culture media. This tradition of perfecting cell culture media lives on at SAFC Biosciences, created when Sigma-Aldrich(www.sial.com) acquired JRH Biosciences in February 2005.
The new plant underscores the company’s commitment to provide critical raw materials to the biopharmaceutical industry, which needs specialized cell culture media to cost-effectively generate Mabs and other biotherapeutics.
The 95,000-sq-ft facility was designed to address future needs for the large-scale manufacturing of biotherapeutics. “If customers commit to you to manufacture a product, they want assurances that you can supply them with raw materials not only today but also 10 to 15 years from now,” says Barb Martinez, production manager.
A two-story tall stainless steel blender at the Lenexa plant mixes up to 4,000-kilogram batches of media, then dispenses them into containers specified by customers. Cell culture media typically contains 50–70 ingredients, including amino acids, vitamins, minerals, and sugars, which consist of different-size particles that may settle during storage or cause solubility problems when hydrated.
To insure homogeneity, a high-speed pin mill pulverizes ingredients to produce uniform particles of a designated size. Experts in process development, quality control, manufacturing, and other specialties ensure that all powder media is scalable, soluble, and consistent.
Evolving Media Needs
Although animal serum has long been a key agent for growing cells in culture, customers now desire serum-free media. The demand is driven by regulatory concerns about prions or other contaminants in media used to manufacture Mabs or vaccine antigens for human use.
Serum consists of a complex mixture of biological components, such as peptides, growth factors, and cytokines. Along with the company’s knowledge and experience of media, analytical tools help to characterize serum. The challenge lies in combining key components to optimize cell culture growth and expression of proteins.
“There’s no one way to replace serum,” says Bruce Lehr, director of marketing. To help customers make the switch, the company offers a library of media that are free of animal components to match customer needs. Even established cell lines change and need new nutrients to tweak protein expression.
A custom formulation manufacturing service, called imMEDIAte Advantage™, quickly manufactures liquid or powder media formulations for customers in about 10 working days. Performed at the customer’s site, imMEDIAte Advantage gives many variations of media for testing and evaluation. The fast turnaround reduces process development timelines.
A huge bottleneck in the development of biologics is selecting cell clones that generate high levels of product. SAFC Biosciences licensed exclusively a select application of LEAP, or laser-enabled analysis and processing, a high-throughput platform that rapidly isolates high-titer cell lines.
LEAP scans cell samples in 384-well microplates coated with an antibody to detect the target protein in 10 minutes. Each well of a plate contains up to 5,000 cells. An algorithm calculates the amount of product secreted and selects the best clone from among millions of cells. Moreover, the laser capability of the LEAP instrument can be tuned to kill all but one cell in a well, ensuring a single cell clone for further expansion and development. LEAP also serves as a microscope to view the growth of clones or cell size and morphology.
“LEAP statistically increases the chance of finding high-producing clones and offers tremendous time and labor savings,” says Kevin Kayser, manager of cell sciences and development at the company’s Life Sciences & High Technology Center in St. Louis, MO.
Within biopharmaceutical development, clone selection remains a tedious manual task lasting a year or more, which LEAP performs in only six months. In the classic process, clones that look promising are diluted so that only one is plated per well, then expanded to test for productivity. “We reverse that order and look for productivity before we expand the clone, so everything selected by LEAP is productive,” Lehr says.
SAFC Biosciences markets the service as Cell Xpress™. In addition to selecting stable clones, the Cell Xpress service formulates media to speed the production of biologics. “We screen the clones with our media to evaluate how productivity increases to find the right media,” says Matt Caple, director of R&D. Customers are spared the long media development process.
The shortage of influenza vaccine during the 2005–2006 season highlighted the flaws of current vaccine manufacturing methods, which rely on chicken eggs or primary chicken embryo fibroblasts. As an alternative, SAFC Biosciences developed the Ex-Cell™ EBx™ system based on a chicken embryonic stem cell line established by Vivalis(www.vivalis.com) in Nantes, France.
SAFC Biosciences designed an exclusive serum-free media to enhance the growth of EBx cells, while preserving the undifferentiated state of the stem cells. EBx cells are easily infected by viruses and generate large quantities of vaccine antigens. The process has been scaled up for large bioreactors.
“Clients who have licensed the cell line take their intellectual property, scale it up, and really run with it,” says Allen Gross, marketing manager of biodevelopment.
The production of biologics requires the cleaning and validation of stainless steel tanks, tubing, and pipelines. “Disposables give people more flexibility and reduce the costs of cleaning and validation,” says Denise DeTommaso, marketing manager for Bioeaze™ biodisposables.
Bioeaze products are suitable for upstream or downstream processes. Custom technical design consultations, validation, and technical support are available. Bioeaze, a system of disposables ranging from 1/8-inch diameter tubing to 2,000-L sterile bags, supports scale-up processes and can reduce investments in stainless steel equipment.
SAFC Biosciences supports about half of the 20 biotherapeutics on the market today as well as hundreds of other firms with biologics in their pipelines. With customers demanding faster results, SAFC “brings together a combination of science innovations and supply chain management,” says Archie Cullen, vp of sales & marketing.